BERKELEY, CA (UroToday.com) - The equivalence of surgical and different pharmacological castrations has been contested, and it is of concern that most of the phase III studies for the Food and Drug Administration licensing of LHRH agonists were based on the previous 50 ng/dl castration level defined by the historical assay limitation, dated before 1996.
Adding to this controversy is a cluster of evidence supporting the hypothesis ‘the lower the better when achieving castration levels of testosterone,’ based on the data from second-line hormonal manipulation and its molecular basis.[1]
Leonardo Oliveira Reis, MD, MSc, PhDUntil now, the optimal serum testosterone level in patients under castration and the impact of its variations in patients under LHRH therapy remained uncertain. In the current scenario of advancements (measured in a few months and under high costs) which are not available to most of the world population, compared with the benefits of hormonal manipulation that are measured in years,[1] this denotes a huge potential for accessible and durable effect expansion and optimization of treatment, particularly for the current tendency of a more individual approach.
We have previously highlighted[1] that although the androgen receptor (AR) is the major therapeutic target of prostate cancer (PCa), there are currently no clinical studies available in which the AR status was considered in the study design. Furthermore, to date, even with better understanding of the molecular pathways behind castration resistant prostate cancer (CRPC), no study on secondary hormonal treatment with strong methodology has shown a benefit in terms of survival, but most trials have been smaller and heavily biased for patients’ heterogeneity.
Adding to this complex and challenging scenario is the fact recently confirmed by our group that the efficiency of the different available pharmacological castration solutions aimed at reaching castration levels, mainly for cutoff ≤20 ng/dl, can vary significantly; surprisingly, about half and one-third of patients did not achieve castration levels of 20 and 50 ng/dl respectively.[2]
It is of concern that although in the last 2 years, three approved treatments based on Phase III trials have demonstrated modest survival improvements (measured in months) in CRPC [cabazitaxel (potent taxane able to bypass the main resistance mechanism to docetaxel drug efflux pump, P-glycoprotein 1; approved in 2010); sipuleucel-T (immunotherapeutic agent through dendritic cells; approved in 2010); and abiraterone (orally active, potent and irreversible inhibitor of CYP17 – a critical enzyme in androgen biosynthesis; approved in 2011)], palpable advancement in hormonal management has been scarce and underexplored.[1,2]
The sequential responses to hormonal manipulation, known as secondary hormonal therapy, implies that AR signaling remains an important therapeutic target and also relies on the fact that CRPC is not necessarily androgen-independent and is susceptible to further hormonal manipulation.[1]
Although an imperative clinical consideration, ineffective testosterone suppression (ITS) through hormonal escape is not recognized when serum testosterone is not systematically monitored, culminating in very scarce data analyzing the impact of serum testosterone levels and breakthrough increases in PCa clinical outcome. Abiraterone, effectively blocking the conversion of androgens from non-gonadal precursors, thus reducing testosterone to undetectable levels, has recently been proved to extend survival rates for men with metastatic CRPC who have progressive disease even after first-line chemotherapy treatment.[1]
Furthermore, when defining CRPC, the specific hormone therapy administered and the response to that therapy can influence the biology of the relapsing tumor and the sensitivity to subsequent therapies, and are therefore fundamental predictors of survival in individual patients. There are unquestionably different molecular determinants on why one cancer would respond to possibly slightly higher androgen levels than another, and this presumably relates to how the AR is working.
Current literature on the issue must be interpreted cautiously once it is not designed based on the above-mentioned rational and does not take into consideration the molecular basis, being obviously not powered to detect small differences in outcome, owing to patients’ heterogeneity and the relatively short median follow-up. Future studies must be based on the proposed rational, with the accurate design of a more individual approach with precise molecular targets, and very long follow-up periods, combined with well-defined and accurate oncological and survival primary outcomes.
References:
- Reis LO 2011 Old issues and new perspectives on prostate cancer hormonal therapy: the molecular substratum. Medical Oncology [In Press]. (doi:10.1007/s12032-011- 9991-z;PMID:21626233)
- Silva ED, Ferreira U, Matheus W, Faria EF, Silva GD, Saito M, de Souza AA, Laranjo A Jr, Clark O, Magna LA, Castilho LN, Reis LO. 2012 Goserelin versus leuprolide in the chemical castration of patients with prostate cancer. International Urology and Nephrology [In Press]. (doi:10.1007/s11255-012-0134-z;PMID:22315155)
Written by:
Leonardo Oliveira Reis, MD, MSc, PhD as part of Beyond the Abstract on UroToday.com. This initiative offers a method of publishing for the professional urology community. Authors are given an opportunity to expand on the circumstances, limitations etc... of their research by referencing the published abstract.
Department of Surgery (Urology)
School of Medical Sciences
University of Campinas, UNICAMP, Brazil
www.fcm.unicamp.br/deptos/urologia
Professor of Medicine (Urology)
Center for Life Sciences
Pontifical Catholic University of Campinas
PUC-Campinas, Brazil
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